Antitumoral carbazoles

Abstract

The invention provides a compound of formula (I). This invention relates to heterocyclic compounds. It further relates to methods for their preparation, compositions cotaining them and their use as a medicament, particularly as a medicament for the treatment and prophylaxis of cancer.

1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         the dotted line represents an optional double bond, with the proviso that at least one single bond is present between C7 and C10; 
         R 1  is selected from hydrogen, C 1-12  alkyl, which may be optionally substituted by a group selected from hydroxyl, C 1-12  alkoxy, C 1-30  alkanoyloxy, optionally substituted C 7-11 , aroyloxy, optionally substituted C 8-16  aralkanoyloxy, halogen, optionally substituted C 6-10  aryl, amino, mono-(C 1-12  alkyl)amino and di-(C 1-12  alkyl)amino; optionally substituted C 6-10  aryl; carboxy; C 1-30  alkoxycarbonyl; optionally substituted C 7-11  aryloxycarbony; optionally substituted C 8-16  aralkyloxycarbonyl; carbamoyl; N—(C 1-12  alkyl)carbamoyl and N,N-di-(C 1-12  alkyl)carbamoyl; 
         R 2a  and R 2b  are independently selected from hydrogen, hydroxy, C 1-12  alkyl, C 1-30  alkanoyl, optionally substituted C 7-11  aroyl, optionally substituted C 8-16  aralkanoyl, C 1-12  alkoxy, C 1-30  alkanoyloxy, optionally substituted C 7-11  aroyloxy and optionally substituted C 8-16  aralkanoyloxy, with the proviso that the substituent R 2b  is absent if a double bond is present between C7 and C8; 
         or R 2a  and R 2b  together represent oxygen; 
         R 3a  and R 3b  are independently selected from hydrogen; halogen; hydroxy; amino; mono-(C 1-12  alkyl)amino; di-(C 1-12  alkyl)amino; C 1-12  alkoxy; C 1-30  alkanoyoxyl; optionally substituted C 7-11  aroyloxy; optionally substituted C 8-16  aralkanoyloxy; C 1-12  alkyl, which may be optionally substituted by a group selected from hydroxy, C 1-12  alkoxy, C 1-30  alkanoyloxy, optionally substituted C 7-11  aroyloxy, optionally substituted C 8-16  aralkanoyloxy, halogen, optionally substituted C 6-10 , aryl, amino, mono-(C 1-12 alkyl)amino and di-(C 1-12  alkyl)amino; optionally substituted C 6-10  aryl; C 1-30  alkanoyl, optionally substituted C 7-11  aroyl; optionally substituted C 8-16  aralkanoyl; carboxy; C 1-30  alkoxycarbonyl; optionally substituted C 7-11  aryloxycarbonyl; optionally substituted C 8-16  aralkyloxycarbonyl; carbamoyl; N—(C 1-12  alkyl) carbamoyl and N,N-di-(C 1-12  alkyl) carbamoyl, with the proviso that the substituent R 3b  is absent if a double bond is present between C9 and C10; 
         or R 3a  and R 3b  together represent oxygen; and 
         R 4  is selected from hydrogen, unsubstituted C 1-12  alkyl, C 1-30  alkanoyl, optionally substituted C 7-11  aroyl and optionally substituted C 8-16  aralkanoyl; 
         or a pharmaceutically acceptable salt thereof, with the exception of the following compounds: 
       
       (a) a compound wherein R 1  is hydrogen or halogen, R 2a , R 2b , R 3a  and R 3b  are all hydrogen, R 4  is hydrogen or lower alkyl, and double bonds are present between C7 and C8 and between C9 and C10; 
       (b) a compound wherein R 1 , R 2a , R 2b , R 3a  and R 3b  are all hydrogen, R 4  is methyl, and double bonds are present between C7 and C8 and between C9 and C10; and 
       (c) a compound wherein R 1 , R 2a , R 2b , R 3a , R 3b  and R 4  are all hydrogen, and no double bonds are present between C7 and C10. 
     
     
       2. A compound according to  claim 1 , wherein R 1  is selected from carboxy, C 1-12  alkoxycarbonyl, carbamoyl, N—(C 1-6  alkyl) carbamoyl and N,N-di-(C 1-6  alkyl) carbamoyl. 
     
     
       3. A compound according to  claim 1 , wherein R 1  is selected from carboxy and C 1-6  alkoxycarbonyl. 
     
     
       4. A compound according to  claim 1 , wherein R 1  is C 1-4  alkoxycarbonyl. 
     
     
       5. A compound according to  claim 1 , wherein R 1  is methoxycarbonyl. 
     
     
       6. A compound according to  claim 1 , wherein R 2a  and R 2b  are independently selected from hydrogen, hydroxy, C 1-6  alkoxy and C 1-12  alkanoyloxy, or R 2a  and R 2b  together represent oxygen. 
     
     
       7. A compound according to  claim 1 , wherein R 2a  and R 2b  are independently selected from hydrogen, hydroxy and C 1-4  alkoxy, or R 2a  and R 2b  together represent oxygen. 
     
     
       8. A compound according to  claim 1 , wherein R 2a  and R 2b  together represent oxygen. 
     
     
       9. A compound according to  claim 1 , wherein R 3a  and R 3b  are independently selected from hydrogen; hydroxy; C 1-6  alkoxyl; C 1-12  alkanoyloxyl; C 1-6  alkyl, which may be optionally substituted by a group selected from hydroxy, C 1-6  alkoxy and C 1-12  alkanoyloxy; C 1-12  alkanoyl; carboxy and C 1-12  alkoxycarbonyl; or R 3a  and R 3b  together represent oxygen. 
     
     
       10. A compound according to  claim 1 , wherein R 3a  and R 3b  are independently selected from hydrogen; hydroxy; C 1-4  alkyl, which is substituted by a group selected from hydroxy and C 1-4  alkoxy; C 1-6  alkanoy; carboxy and C 1-6  alkoxycarbonyl. 
     
     
       11. A compound according to  claim 1 , wherein R 3a  and R 3b  are independently selected from hydroxy, hydroxymethyl, C 1-4  alkanol and carboxy. 
     
     
       12. A compound according to  claim 1 , wherein one of R 3a  and R 3b  is hydroxy and the other is formyl. 
     
     
       13. A compound according to  claim 1 , wherein a double bond is present between C8 and C9. 
     
     
       14. A compound according to  claim 1 , wherein double bonds are present between C7 and C8 and between C9 and C10. 
     
     
       15. 8-formyl-8,9-dihydroxy-5-oxo-8,9-dihydro-5H-carbazole-1-carboxylic acid methyl ester, which is coproverdine, and pharmaceutically acceptable salts thereof according to  claim 1 . 
     
     
       16. A pharmaceutical preparation which contains as active ingredient a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
       17. A method for the treatment of lung cancer, prostate cancer, colon cancer, leukemia, or melanoma in a mammal, comprising administering to the affected individual an effective amount of a compound of formula (I); 
       
         
           
           
               
               
           
         
         wherein 
         the dotted line represents an optional double bond, with the proviso that at least one single bond is present between C7 and C10; 
         R 1  is selected from hydrogen: C 1-12  alkyl, which may be optionally substituted by a group selected from hydroxyl, C 1-12  alkoxy, C 1-30  alkanoyloxy, optionally substituted C 7-11 , aroyloxy, optionally substituted C 8-16  aralkanoyloxy, halogen, optionally substituted C 6-10  aryl, amino, mono-(C 1-12  alkyl)amino and di-(C 1-12  alkyl)amino: optionally substituted C 6-10  aryl; carboxy; C 1-30  alkoxycarbonyl; optionally substituted C 7-11  aryloxycarbonyl; optionally substituted C 8-16  aralkyloxycarbonyl; carbamoyl; N—(C 1-12  alkyl)carbamoyl and N,N-di-(C 1-12  alkyl)carbamoyl; 
         R 2a  and R 2b  are independently selected from hydrogen, hydroxy, C 1-12  alkyl, C 1-30  alkanoyl, optionally substituted C 7-11  aroyl, optionally substituted C 8-16  aralkanoyl, C 1-12  alkoxy, C 1-30  alkanoyloxy, optionally substituted C 7-11  aroyloxy and optionally substituted C 8-16  aralkanoyloxy, with the proviso that the substituent R 2b  is absent if a double bond is present between C7 and C8; 
         or R 2a  and R 2b  together represent oxygen; 
         R 3a  and R 3b  are independently selected from hydrogen; halogen; hydroxy; amino; mono-(C 1-12  alkyl)amino; di-(C 1-12  alkyl)amino; C 1-12  alkoxy; C 1-30  alkanoyloxy; optionally substituted C 7-11  aroyloxy, optionally substituted C 8-16  aralkanoyloxy; C 1-12  alkyl, which may be optionally substituted by a group selected from hydroxy, C 1-12  alkoxy, C 1-30  alkanoyloxy, optionally substituted C 7-11  aroyloxy, optionally substituted C 8-16  aralkanoyloxy, halogen, optionally substituted C 6-10 , aryl, amino, mono-(C 1-12  alkyl)amino and di-(C 1-12  alkyl)amino; optionally substituted C 6-10  aryl; C 1-30  alkanoyl, optionally substituted C 7-11  aroyl; optionally substituted C 8-16  aralkanoyl; carboxy; C 1-30  alkoxycarbonyl; optionally substituted C 7-11  aryloxycarbonyl; optionally substituted C 8-16  aralkyloxycarbonyl; carbamoyl; N—(C 1-12  alkyl) carbamoyl and N,N-di-(C 1-12  alkyl) carbamoyl, with the proviso that the substituent R 3b  is absent if a double bond is present between C9 and C10; 
         or R 3a  and R 3b  together represent oxygen; and 
         R 4  is selected from hydrogen, C 1-12  alkyl, C 1-30  alkanoyl, optionally substituted C 7-11  aroyl and optionally substituted C 8-16  aralkanoyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       18. A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         the dotted line represents an optional double bond, with the proviso that at least one single bond is present between C7 and C10; 
         R 1  is selected from C 1-12  alkyl, which may be optionally substituted by a group selected from hydroxyl, C 1-12  alkoxy, C 1-30  alkanoyloxy, optionally substituted C 7-11 , aroyloxy, optionally substituted C 8-16  aralkanoyloxy, halogen, optionally substituted C 6-10  aryl, amino, mono-(C 1-12 alkyl)amino and di-(C 1-12  alkyl)amino; optionally substituted C 6-10  aryl; carboxy; C 1-30  alkoxycarbonyl; optionally substituted C 7-11  aryloxycarbonyl; optionally substituted C 8-16  aralkyloxycarbonyl; carbamoyl; N—(C 1-12  alkyl)carbamoyl and N,N-di-(C 1-12  alkyl)carbamoyl; 
         R 2a  and R 2b  are independently selected from hydrogen, hydroxy, C 1-12  alkyl, C 1-30  alkanoyl, optionally substituted C 7-11  aroyl, optionally substituted C 8-16  aralkanoyl, C 1-12  alkoxy, C 1-30  alkanoyloxy, optionally substituted C 7-11  aroyloxy and optionally substituted C 8-16  aralkanoyloxy, with the proviso that the substituent R 2b  is absent if a double bond is present between C7 and C8; 
         or R 2a and R 2b  together represent oxygen; 
         R 3a  and R 3b  are independently selected from hydrogen; halogen; hydroxy; amino; mono-(C 1-12  alkyl)amino; di-(C 1-12  alkyl)amino; C 1-12  alkoxy; C 1-30  alkanoyloxy; optionally substituted C 7-11  aroyloxy; optionally substituted C 8-16  aralkanoyloxy; C 1-12  alkyl, which may be optionally substituted by a group selected from hydroxy, C 1-12  alkoxy, C 1-30  alkanoyloxy, optionally substituted C 7-11  aroyloxy, optionally substituted C 8-16  aralkanoyloxy, halogen, optionally substituted C 6-10 , aryl, amino, mono-(C 1-12  alkyl)amino and di-(C 1-12  alkyl)amino; optionally substituted C 6-10  aryl; C 1-30  alkanoyl, optionally substituted C 7-11  aroyl; optionally substituted C 8-16  aralkanoyl; carboxy; C 1-30  alkoxycarbonyl; optionally substituted C 7-11  aryloxycarbonyl; optionally substituted C 8-16  aralkyloxycarbonyl; carbamoyl; N—(C 1-12  alkyl) carbamoyl and N,N-di-(C 1-12  alkyl) carbamoyl, with the proviso that the substituent R 3b  is absent if a double bond is present between C9 and C10; 
         or R 3a  and R 3b  together represent oxygen; and 
         R 4  is selected from hydrogen, C 1-12  alkyl, C 1-30  alkanoyl, optionally substituted C 7-11  aroyl and optionally substituted C 8-16  aralkanoyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       19. A compound according to  claim 18 , wherein R 2a  and R 2b  are independently selected from hydrogen, hydroxy, C 1-6  alkoxy and C 1-12  alkanoyloxy, or R 2a  and R 2b  together represent oxygen. 
     
     
       20. A compound according to  claim 18 , wherein R 2a  and R 2b  are independently selected from hydrogen, hydroxy and C 1-4  alkoxy, or R 2a  and R 2b  together represent oxygen. 
     
     
       21. A compound according to  claim 18 , wherein R 2a  and R 2b  together represent oxygen. 
     
     
       22. A compound according to  claim 18 , wherein R 3a  and R 3b  are independently selected from hydrogen; hydroxy; C 1-6  alkoxy; C 1-12  alkanoyloxy; C 1-6  alkyl, which may be optionally substituted by a group selected from hydroxy, C 1-6  alkoxy and C 1-12  alkanoyloxy; C 1-12  alkanoyl; carboxy and C 1-12  alkoxycarbonyl; or R 3a  and R 3b  together represent oxygen. 
     
     
       23. A compound according to  claim 18 , wherein R 3a  and R 3b  are independently selected from hydrogen; hydroxy; C 1-4  alkyl, which is substituted by a group selected from hydroxy and C 1-4  alkoxy; C 1-6  alkanoyl; carboxy and C 1-6  alkoxycarbonyl. 
     
     
       24. A compound according to  claim 18 , wherein R 2a  and R 2b  independently selected from hydroxy, hydroxymethyl, C 1-4  alkanol and carboxy. 
     
     
       25. A compound according to  claim 18 , wherein one of R 2a  and R 3b  is hydroxy and the other is formyl. 
     
     
       26. A compound according to  claim 18 , wherein a double bond is present between C8 and C9. 
     
     
       27. A compound according to  claim 18 , wherein double bonds are present between C7 and C8 and between C9 and C10. 
     
     
       28. A pharmaceutical preparation which contains as active ingredient a compound according to  claim 18 , or a pharmaceutically acceptable salt thereof.